Common variable immunodeficiency (CVID) comprises the most clinically important primary immunodeficiency due to its prevalence, serious complications and long---term costs of therapy. A form of interstitial lung disease (ILD) known as granulomatous/lymphocytic interstitial lung disease (GLILD) occurs in 10---15% of patients with CVID. In our experience, GLILD causes progressive restrictive lung disease, leads to substantial morbidity, and is an important cause of death. The causes of GLILD are unknown, no long---term longitudinal study has defined the natural course of GLILD, and no clinical trials have been performed to define an optimal therapeutic regimen for this condition. Consequently, there is no established standard of care for the treatment of GLILD. We recently found that immunosuppressive therapy using rituximab (RTX), a monoclonal antibody against the B cell antigen CD20, and an anti---metabolite, azathioprine (AZA), improved the pulmonary function and radiographic abnormalities seen on high resolution CT (HRCT) scans of the chest in select cohort of patients with GLILD. Given these encouraging results, we propose a multicenter, placebo controlled trial for patients with GLILD. Study patients will receive either placebo, or RTX and AZA for 18 months. We will measure the effect of treatment on pulmonary function and HRCT. In parallel, we will perform RNA-seq on open lung biopsies of patients with GLILD or normal lung, and determine if the transcriptome of lungs of patients with GLILD are distinct and predictive of those patients that respond or don't respond to RTX/AZA. We will use RNA-seq differential expression in combination with novel software known as PRICE (Paired---Read Iterative Contig Extension) to screen open lung biopsies for potential pathogens that cause GLILD. Finally, we will determine if decreases in the percentage of DR+T cells, and increases in the number of Tregs in the peripheral blood, are predictors of response to RTX/AZA. The goals of the R34 planning grant are to: 1) Ensure feasibility of conducting the proposed trial by recruiting sufficient investigators and centers; 2) Develop the structure whereby the trial may be conducted. This will include, but not be limited to, development of a leadership structure; clinica and scientific cores; regulatory documents; Data safety monitoring board (DSMB); Manuals of Procedures (MOP); and databases for collection of data to ensure scientific and ethical rigor; 3) Establish a consensus on the remaining clinical and scientific issues as it relates to the three aims of the proposed clinical trial.